阅读说明：本技术 一种来氟米特晶型i的制备方法 (Preparation method of leflunomide crystal form I ) 是由 冯芮茂 奚灏瀛 张成海 于 2021-02-04 设计创作，主要内容包括：本发明涉及药物晶型领域,具体涉及一种来氟米特晶型I的制备方法,具体包括以下步骤：1)将来氟米特溶解于C1-C4的醇类溶剂和二甲基亚砜的混合溶剂,或将来氟米特溶于C1-C4的醇类溶剂、二甲基亚砜和水的混合溶剂；2)降温析出晶体,过滤得到固体,固体干燥得到来氟米特晶型I。本发明提供的晶型I制备方法,避免了晶型I生产过程中出现混晶,制备得到晶体粒度较小,稳定性好,压片后的制剂产品溶出度较高。(The invention relates to the field of pharmaceutical crystal forms, in particular to a preparation method of leflunomide crystal form I, which comprises the following steps: 1) dissolving leflunomide in a mixed solvent of an alcohol solvent with C1-C4 and dimethyl sulfoxide, or dissolving leflunomide in a mixed solvent of an alcohol solvent with C1-C4, dimethyl sulfoxide and water; 2) and cooling to separate out crystals, filtering to obtain a solid, and drying the solid to obtain the leflunomide crystal form I. The preparation method of the crystal form I provided by the invention avoids mixed crystals in the production process of the crystal form I, the prepared crystals have smaller granularity and good stability, and the prepared preparation product has higher dissolution rate after tabletting.)

1. A method for preparing leflunomide crystalline form I, comprising the steps of:

1) dissolving leflunomide in a mixed solvent of an alcohol solvent with C1-C4 and dimethyl sulfoxide, or dissolving leflunomide in a mixed solvent of an alcohol solvent with C1-C4, dimethyl sulfoxide and water;

2) and cooling to separate out crystals, filtering to obtain a solid, and drying the solid to obtain the leflunomide crystal form I.

2. The method of claim 1, comprising the steps of:

1) heating leflunomide to dissolve in a mixed solvent of an alcohol solvent of C1-C4 and dimethyl sulfoxide, or heating leflunomide to dissolve in a mixed solvent of an alcohol solvent of C1-C4, dimethyl sulfoxide and water;

2) diluting the obtained solution with water to ensure that the volume ratio of the organic solvent to the water is 1: 1.0-1: 5.0, preferably 1: 2.5;

3) and cooling to separate out crystals, filtering to obtain a solid, and drying the solid to obtain the leflunomide crystal form I.

3. The process according to claim 1, wherein the C1-C4 alcoholic solvent is selected from methanol, ethanol or isopropanol, preferably ethanol.

4. The method according to claim 1, wherein the volume ratio of the C1-C4 alcohol solvent to the dimethyl sulfoxide is 10: 1-1: 1, preferably 3: 1-5: 1.

5. The method according to claim 1, wherein the temperature for cooling to precipitate the crystals is 0 to 40 ℃, preferably 0 to 10 ℃.

6. The method according to claim 2, wherein the heating and dissolving temperature is 40 to 100 ℃, preferably 50 to 70 ℃.

Technical Field

The invention relates to the field of pharmaceutical crystal forms, and in particular relates to a preparation method of leflunomide crystal form I.

Background

Leflunomide tablets are isoxazole immunosuppressants with antiproliferative activity which are firstly developed by Aventis Pharma and are used for treating diseases such as adult rheumatoid arthritis, psoriasis, systemic lupus erythematosus and the like.

Four crystal forms of leflunomide are currently reported. Crystal form I and crystal form II are reported in patent application CN 1208034A. Form I has a specific X-ray diffraction pattern with strong diffraction peaks at 2 theta angles of 16.70 °, 18.90 °, 23.00 °, 23.65 °, and 29.05 °, and weak diffraction peaks at 2 theta angles of 8.25 °, 12.65 °, 15.00 °, 15.30 °, 18.35 °, 21.25 °, 22.15 °, 24.10 °, 24.65 °, 25.45 °, 26.65 °, 27.40 °, 28.00 °, and 28.30 °. The crystal form II has specific diffraction peaks, strong diffraction peaks exist at 2 theta angles of 10.65 degrees, 14.20 degrees, 14.80 degrees, 16.10 degrees, 21.70 degrees, 23.15 degrees, 24.40 degrees, 24.85 degrees, 25.50 degrees, 25.85 degrees, 26.90 degrees and 29.85 degrees, and weak diffraction peaks exist at 7.40 degrees, 9.80 degrees, 13.10 degrees, 15.45 degrees, 16.80 degrees, 20.70 degrees, 21.45 degrees, 22.80 degrees, 23.85 degrees, 27.25 degrees and 28.95 degrees. Patent application CN00817283 reports crystal form III, which is a solvent compound of N-methylpyrrolidone, and is not suitable for pharmaceutical use. Patent CN107311954A reports form IV, which has an upper 2 θ angle in the XRD pattern: the diffraction peak is characterized at 8.04 DEG plus or minus 0.2 DEG, 10.83 DEG plus or minus 0.2 DEG, 14.29 DEG plus or minus 0.2 DEG, 18.72 DEG plus or minus 0.2 DEG, 20.48 DEG plus or minus 0.2 DEG and 24.92 DEG plus or minus 0.2 deg.

Form I slowly converts to form II at 10-40 ℃. Form II converts to form I above 50 ℃. The crystal form I can be slowly converted into the crystal form II at room temperature, and the crystal form II is converted into the crystal form I at high temperature. Most of the raw material medicines in the current market are mixed crystals of a crystal form I and a crystal form II, which not only influences the production quality of the raw material medicines and the preparation, but also influences the stability of the preparation. Form IV has better stability under high light conditions at room temperature and high humidity and temperature, but according to the thermodynamic principle, a stable form generally has low solubility. The crystal form with low solubility has relatively good stability at the same temperature. Although the solubility of the crystal form I, the crystal form II and the crystal form IV of leflunomide in various media is very low, and the leflunomide belongs to insoluble drugs, the solubility of the crystal form IV is the lowest, and the crystal dissolution speed and the dissolution rate of a preparation product are greatly influenced by crystal form IV particles, so that the development of the preparation is not facilitated.

Patent CN1208034A reports that the crystalline form I of leflunomide is prepared by adding leflunomide which does not exist in form I or a mixture of form I and other forms of leflunomide to an organic solvent or a mixture of an organic solvent and water, heating the obtained mixture to 41 ℃ to the boiling point of the organic solvent, diluting the obtained solution with water or distilling off the organic solvent to make the ratio of the organic solvent to water 4:1 to 0.3:1, and crystallizing at a temperature above 40 ℃. Higher temperature crystallization has larger influence on the crystallization yield of leflunomide.

Based on the situation, the crystal form of leflunomide with high stability and the preparation method thereof are screened and developed, and the method has great significance for the development of leflunomide medicaments.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a preparation method of leflunomide crystal form I, which comprises the following steps:

1) dissolving leflunomide in a mixed solvent of an alcohol solvent with C1-C4 and dimethyl sulfoxide, or dissolving leflunomide in a mixed solvent of an alcohol solvent with C1-C4, dimethyl sulfoxide and water;

2) and cooling to separate out crystals, filtering to obtain a solid, and drying the solid to obtain the leflunomide crystal form I.

The preparation method of the preferred leflunomide crystal form I comprises the following steps:

1) heating leflunomide to dissolve in a mixed solvent of an alcohol solvent of C1-C4 and dimethyl sulfoxide, or heating leflunomide to dissolve in a mixed solvent of an alcohol solvent of C1-C4, dimethyl sulfoxide and water;

2) diluting the obtained solution with water to ensure that the volume ratio of the organic solvent to the water is 1: 1.0-1: 5.0, preferably 1: 2.5;

3) and (3) cooling to 0-10 ℃ to separate out crystals, filtering to obtain a solid, and drying the solid to obtain the leflunomide crystal form I.

Wherein the volume ratio of the C1-C4 alcohol solvent to the dimethyl sulfoxide is 10: 1-1: 1, preferably 3: 1-5: 1.

Wherein the heating and dissolving temperature is 40-100 ℃, preferably 50-70 ℃.

Wherein the temperature for cooling and precipitating crystals is 0-40 ℃, and preferably 0-10 ℃.

Wherein the C1-C4 alcohol solvent is selected from methanol, ethanol or isopropanol, preferably ethanol.

The invention has the beneficial effects that: the preparation method of the crystal form I provided by the invention avoids mixed crystals in the production process of the crystal form I, and the prepared crystal has smaller granularity, good stability and higher dissolution rate of the pressed preparation product.

Drawings

FIG. 1 is an XRD pattern of leflunomide form I;

FIG. 2 is an XRD pattern of a mixed crystal of leflunomide form I and form II;

FIG. 3 is a particle size distribution diagram of leflunomide prepared in example 5;

FIG. 4 is a particle size distribution diagram of leflunomide prepared in comparative example 2;

FIG. 5 is a particle size distribution diagram of leflunomide prepared in comparative example 3.

Detailed Description

Hereinafter, embodiments of the present invention will be described in detail in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be noted that the embodiments and features of the embodiments in the present application may be arbitrarily combined with each other without conflict.

Comparative example 1: CN107311954A example 16

Separately, iv0.5g leflunomide crystal form, 6.2g lactose, 0.75g crospovidone, 25mg silicon dioxide and 25mg magnesium stearate were weighed. And sequentially adding lactose and crospovidone into the leflunomide crystal form IV, then adding silicon dioxide and magnesium stearate, and manually and uniformly mixing. And (3) adjusting a tablet press to ensure that the tablet weight is about 150mg, and directly performing dry direct compression to obtain the leflunomide crystal form IV tablet, wherein the dissolution rate of the leflunomide crystal form IV tablet in pure water for 30 minutes can reach 80%.

Comparative example 2: example 4 of CN1208034A was repeated

Leflunomide was dissolved in isopropanol/water (equivalent to a mixed solution of leflunomide 160g dry dissolved in 280ml isopropanol and 90ml water). The mixture was heated to 78 ℃ to 80 ℃, stirred at this temperature for 25 minutes, and then filtered through a pressure funnel into a vessel that had been heated to the same temperature. The pressure funnel was rinsed with 80ml of isopropanol, and the isopropanol used was added to give an isopropanol/water ratio of 4: 1. Then, water (360ml, isopropanol/water 0.8: 1) preheated to 78 ℃ to 82 ℃ was added. The solution had become cloudy and was then cooled to 65 ℃ over 20 minutes, held at this temperature for about 40 minutes, cooled to about 40 ℃ over 70 minutes and stirred for an additional 20 minutes, the product was centrifuged and the leflunomide form I was vacuum dried.

Comparative example 3

Adding 100g of leflunomide into 200ml of ethanol, heating to 55-60 ℃ for dissolving, adding 500ml of room-temperature purified water at a constant speed, cooling to 0-10 ℃ after 5 minutes of addition, stirring for crystallization for 2 hours, filtering, washing a filter cake with a proper amount of water, and drying in vacuum to obtain 93.7g of leflunomide crystals with a yield of 93.7%.

Example 1

Adding 100g of leflunomide into 200ml of ethanol-DMSO (volume ratio of 4:1) mixed solution, heating to 55-60 ℃ for dissolving, adding 200ml of room-temperature purified water at a constant speed, cooling to 10-20 ℃ after 5 minutes of addition, stirring for crystallization for 2 hours, filtering, washing a filter cake with a proper amount of water, and drying in vacuum to obtain 91.2g of leflunomide crystal form I with the yield of 91.2%.

Example 2

Adding 100g of leflunomide into 200ml of ethanol-DMSO (volume ratio of 4:1) mixed solution, heating to 55-60 ℃ for dissolving, adding 500ml of room-temperature purified water at a constant speed, cooling to 0-10 ℃ after 5 minutes of addition, stirring for crystallization for 2 hours, filtering, washing a filter cake with a proper amount of water, and drying in vacuum to obtain 94.0g of leflunomide crystal form I with the yield of 94.0%.

Example 3

Adding 100g of leflunomide into 200ml of ethanol-DMSO (volume ratio of 4:1) mixed solution, heating to 55-60 ℃ for dissolving, adding 1000ml of room-temperature purified water at a constant speed, cooling to 0-10 ℃ after 5 minutes of addition, stirring for crystallization for 2 hours, filtering, washing a filter cake with a proper amount of water, and drying in vacuum to obtain 94.7g of leflunomide crystal form I with the yield of 94.7%.

Example 4

Adding 100g of leflunomide into 200ml of ethanol-DMSO (volume ratio of 3:1) mixed solution, heating to 55-60 ℃ for dissolving, adding 500ml of room-temperature purified water at a constant speed, cooling to 0-10 ℃ after 5 minutes of addition, stirring for crystallization for 2 hours, filtering, washing a filter cake with a proper amount of water, and drying in vacuum to obtain 94.2g of leflunomide crystal form I with the yield of 94.2%.

Example 5

Adding 100g of leflunomide into 200ml of ethanol-DMSO (volume ratio of 4:1) mixed solution, heating to 55-60 ℃ for dissolving, adding 500ml of room-temperature purified water at a constant speed, cooling to 0-10 ℃ after 5 minutes of addition, stirring for crystallization for 2 hours, filtering, washing a filter cake with a proper amount of water, and drying in vacuum to obtain 94.5g of leflunomide crystal form I with the yield of 94.5%.

Example 6

Adding 100g of leflunomide into 200ml of ethanol-DMSO (volume ratio 6:1) mixed solution, heating to 55-60 ℃ for dissolving, adding 500ml of room-temperature purified water at a constant speed, cooling to 0-10 ℃ after 5 minutes of addition, stirring for crystallization for 2 hours, filtering, washing a filter cake with a proper amount of water, and drying in vacuum to obtain 94.0g of leflunomide crystal form I with the yield of 94.0%.

Example 7

Adding 100g of leflunomide into 200ml of ethanol-DMSO (volume ratio 6:1) mixed solution, heating to 55-60 ℃ for dissolving, adding 500ml of room-temperature purified water at a constant speed, cooling to 0-10 ℃ after 5 minutes of addition, stirring for crystallization for 2 hours, filtering, washing a filter cake with a proper amount of water, and drying in vacuum to obtain 94.0g of leflunomide crystal form I with the yield of 94.0%.

Example 8

Adding 100g of leflunomide into 200ml of ethanol-DMSO (volume ratio of 4:1) mixed solution, heating to 55-60 ℃ for clearing, adding 500ml of room-temperature purified water at a constant speed, cooling to 30-35 ℃ after 5 minutes of addition, stirring for crystallization for 2 hours, filtering, washing a filter cake with a proper amount of water, and drying in vacuum to obtain 84.2g of leflunomide crystal form I with the yield of 84.2%.

Experimental example 1: crystal form detection

The leflunomide prepared in comparative example 2, comparative example 3 and examples 1 to 8 was taken and subjected to XRD detection. Wherein, XRD patterns of the samples of examples 1-8 and comparative example 2 are shown in figure 1, and the samples are pure crystal form I. The XRD pattern of the sample of comparative example 2 is shown in figure 2 and is a mixed crystal of a crystal form I and a crystal form II of the fluoromethite.

Experimental example 2: dissolution testing

Leflunomide tablets were prepared from leflunomide form I prepared in example 5 following exactly the procedure of comparative example 1, and the dissolution in pure water was measured for 30 minutes using leflunomide tablets marketed in the united states (trade name "Arava") as a reference formulation. The determination method is determined according to the second method of 'dissolution and release determination' in the 2020 edition of Chinese pharmacopoeia, wherein the dissolution medium is water, the rotating speed is 100 revolutions per minute, and samples are taken after 30 and 45 minutes.

The dissolution rate of the tablet prepared in the comparative example 1 in pure water for 30 minutes is 80.3%; after the crystal form of example 5 is tabletted, the dissolution rate in pure water for 30 minutes is 94.3%; the dissolution rate of the reference preparation in pure water for 30 minutes is 94.1%.

Experimental example 3: particle size detection

The particle size was determined using malvern 2000 on samples of comparative example 2, comparative example 3 and example 5. The particle size detection pattern of example 5 is shown in FIG. 3, the particle size detection pattern of comparative example 2 is shown in FIG. 4, the particle size detection pattern of comparative example 3 is shown in FIG. 5, and the measurement data are as follows:

	comparative example 2	Comparative example 3	Example 5
				d(0.5)	179.089μm	135.845μm	9.238μm
d(0.9)	406.858μm	370.597μm	27.656μm